Lymphoma David Lee MD, FRCPC

Overview Concepts, classification, biology Epidemiology Clinical presentation Diagnosis Staging Three important types of lymphoma

Conceptualizing lymphoma neoplasms of lymphoid origin, typically causing lymphadenopathy leukemia vs lymphoma lymphomas as clonal expansions of cells at certain developmental stages

ALLMMCLLLymphomas Hematopoietic stem cell Neutrophils Eosinophils Basophils Monocytes Platelets Red cells Myeloid progenitor Myeloproliferative disorders AML Lymphoid progenitor T-lymphocytes Plasma cells B-lymphocytes naïve

B-cell development stem cell lymphoid progenitor progenitor-B pre-B immature B-cell memory B-cell plasma cell DLBCL, FL, HL ALL CLL MM germinalcenterB-cell mature naive B-cell

Clinically useful classification Diseases that have distinct clinical features natural history prognosis treatment Biologically rational classification Diseases that have distinct morphology immunophenotype genetic features clinical features Classification

Lymphoma classification (2001 WHO) B-cell neoplasms –precursor –mature T-cell & NK-cell neoplasms –precursor –mature Hodgkin lymphoma Non- Hodgkin Lymphomas

A practical way to think of lymphoma CategorySurvival of untreated patients CurabilityTo treat or not to treat Non- Hodgkin lymphoma IndolentYearsGenerally not curable Generally defer Rx if asymptomatic AggressiveMonthsCurable in some Treat Very aggressive WeeksCurable in some Treat Hodgkin lymphoma All typesVariable – months to years Curable in most Treat

Mechanisms of lymphomagenesis Genetic alterations Infection Antigen stimulation Immunosuppression

Epidemiology of lymphomas 5 th most frequently diagnosed cancer in both sexes males > females incidence –NHL increasing –Hodgkin lymphoma stable

Incidence of lymphomas in comparison with other cancers in Canada

Age distribution of new NHL cases in Canada

Age distribution of new Hodgkin lymphoma cases in Canada

Risk factors for NHL immunosuppression or immunodeficiency connective tissue disease family history of lymphoma infectious agents ionizing radiation

Clinical manifestations Variable severity: asymptomatic to extremely ill time course: evolution over weeks, months, or years Systemic manifestations fever, night sweats, weight loss, anorexia, pruritis Local manifestations lymphadenopathy, splenomegaly most common any tissue potentially can be infiltrated

Other complications of lymphoma bone marrow failure (infiltration) CNS infiltration immune hemolysis or thrombocytopenia compression of structures (eg spinal cord, ureters) pleural/pericardial effusions, ascites

Diagnosis requires an adequate biopsy Diagnosis should be biopsy-proven before treatment is initiated Need enough tissue to assess cells and architecture –open bx vs core needle bx vs FNA

Stage IStage IIStage IIIStage IV Staging of lymphoma A: absence of B symptoms B: fever, night sweats, weight loss

Three common lymphomas Follicular lymphoma Diffuse large B-cell lymphoma Hodgkin lymphoma

Relative frequencies of different lymphomas Hodgkin lymphoma NHL Diffuse large B-cell Follicular Other NHL Non-Hodgkin Lymphomas ~85% of NHL are B-lineage

Follicular lymphoma most common type of “indolent” lymphoma usually widespread at presentation often asymptomatic not curable (some exceptions) associated with BCL-2 gene rearrangement [t(14;18)] cell of origin: germinal center B-cell

defer treatment if asymptomatic (“watch-and-wait”) several chemotherapy options if symptomatic median survival: years despite “indolent” label, morbidity and mortality can be considerable transformation to aggressive lymphoma can occur

Diffuse large B-cell lymphoma most common type of “aggressive” lymphoma usually symptomatic extranodal involvement is common cell of origin: germinal center B-cell treatment should be offered curable in ~ 40%

Hodgkin lymphoma Thomas Hodgkin ( )

Classical Hodgkin Lymphoma

Hodgkin lymphoma cell of origin: germinal centre B-cell Reed-Sternberg cells (or RS variants) in the affected tissues most cells in affected lymph node are polyclonal reactive lymphoid cells, not neoplastic cells

Reed-Sternberg cell

RS cell and variants popcorn celllacunar cellclassic RS cell (mixed cellularity)(nodular sclerosis) (lymphocyte predominance)

A possible model of pathogenesis germinal centre B cell transforming event(s) loss of apoptosis RS cell inflammatory response EBV? cytokines

Hodgkin lymphoma Histologic subtypes Classical Hodgkin lymphoma –nodular sclerosis (most common subtype) –mixed cellularity –lymphocyte-rich –lymphocyte depleted

Epidemiology less frequent than non-Hodgkin lymphoma overall M>F peak incidence in 3rd decade

Associated (etiological?) factors EBV infection smaller family size higher socio-economic status caucasian > non-caucasian possible genetic predisposition other: HIV? occupation? herbicides?

Clinical manifestations: lymphadenopathy contiguous spread extranodal sites relatively uncommon except in advanced disease “B” symptoms

Treatment and Prognosis StageTreatmentFailure- free survival Overall 5 year survival I,IIABVD x 4 & radiation 70-80%80-90% III,IVABVD x %70-80%

Long term complications of treatment infertility –MOPP > ABVD; males > females –sperm banking should be discussed –premature menopause secondary malignancy –skin, AML, lung, MDS, NHL, thyroid, breast... cardiac disease

Overview Concepts, classification, biology Epidemiology Clinical presentation Diagnosis Staging Three important types of lymphoma